Opioids are effective analgesics. However, their use is associated with a number of undesirable side effects. One such effect is constipation. Opioid-induced changes in gastrointestinal motility are almost universal when these drugs are used to treat pain, and at times may limit their use, leaving the patient in pain. Common treatments of bulking agents and laxatives have limited efficacy and may be associated with side effects such as electrolyte imbalances.
One treatment for opioid side effects is the use of opioid antagonists which cross the blood-brain-barrier, or which are administered directly into the central nervous system. Opioid antagonists such as naltrexone and naloxone have been administered intramuscularly or orally to treat opioid induced side effects. Naltrexone and naloxone are highly lipid soluble and rapidly diffuse across biological membranes, including the blood-brain barrier. However, naltrexone, naloxone, nalmefene, and other opioid antagonists which may reverse many opioid side effects have a narrow therapeutic window before they are observed to reverse the desired analgesic effect of the opioid being used.
Many quaternary amine opioid antagonist derivatives, such as methylnaltrexone, do not reduce the analgesic effect of opioids. These quaternary amine opioid antagonist derivatives, which have a relatively higher polarity and reduced lipid solubility when compared to the tertiary forms of the drugs, were specifically developed to not traverse the blood-brain barrier or to traverse it at a greatly reduced rate. However, high levels of MNTX in the plasma can lead to undesirable side effects such as orthostatic hypotension.
It is desirable in the treatment of many conditions to have oral medications with prolonged effects. Such oral medications are particularly desirable for the treatment of opioid-induced side effects.
It is further desirable to develop a method for the prevention of opioid-induced inhibition of gut motility and constipation which does not counteract the analgesic effects of the opioid, or risk increased levels of pain. Ideally, such a treatment has few side effects either due to low drug toxicity or because administration of small amounts are effective and/or administration results in low circulating levels of the drug.